Mario C. Rico, MD, is an Associate Scientist at Temple University School of Medicine (TUSM) whose career goal is to become an Independent Investigator. Dr. Rico completed his Post-Doctoral Fellowship in bone research and for the last three years has been expanding his experience in the area of thrombosis and hemostasis. Currently he is studying the molecular mechanisms responsible for the increased cardiovascular risk observed in autoimmune diseases such as Rheumatoid Arthritis (RA). The proposed Mentored Career Development Award (K01) will provide the required support to make possible Dr. Rico's successful career in translational medicine in hematological research. Drs. Kunapuli and DeLa Cadena, Professors at TUSM, will mentor the PI. They are well-recognized trainers and established investigators who will guide Dr. Rico's career development. The proposed training plan includes activities to improve the candidate's knowledge and experience in translational medicine in the area of thrombosis and hemostasis. There is generous institutional support to offer him a unique atmosphere to establish a scientific foundation to accomplish his goals. Dr. Rico's long-term research objective is to study the hematologic changes associated with chronic inflammation in autoimmune diseases and other human conditions that are associated with an increased cardiovascular risk. The alpha granules of platelets contain thrombospondin-1 (TSP1) and transforming growth factor beta (TGFb), which are anti-angiogenic and anti-inflammatory molecules, respectively. Paradoxically, excess secretion of these molecules, both systemically and locally in the joint tissue, seems to aggravate the inflammatory process in RA. TSP1 promotes the assembly of the prothrombinase complex on cell surfaces with subsequent generation of serine proteases. Therefore, we propose that high levels of TSP1 in plasma and synovial fluid are responsible in part for the inflammatory changes observed in RA through promotion of assembly of the prothrombinase complex and activation of the TGFb pathway follow by upregulation of connective tissue growth factor (CTGF). CTGF may increase the risk of cardiovascular disease in RA patients. We will investigate the role of a novel pro-inflammatory axis comprised of TSP1, TGFb and CTGF in RA and the contribution provided by platelets, leukocytes and synoviocytes for the axis to be assembled. The aims of the research project are to study the platelet- leukocyte interactions in inflammation resulting in TSP1 and TGFb platelet release and to delineate signaling pathways that leads to CTGF upregulation and expression in leukocytes and synoviocytes. These pathways will be assessed as well in an animal model of erosive arthritis and in samples collected from RA patients. PUBLIC HEALTH RELEVANCE: Chronic diseases affect the quality of life for 133 million Americans and are responsible for seven out of every ten deaths in the U.S.- killing more than 1.7 million Americans every year. Rheumatoid Arthritis (RA) is a chronic disease that affects more than 2 million adults in the United States. This project will investigate the molecular mechanisms related with the increase risk of cardiovascular events in patients afflicted with RA.